Mechanism for activation of mutated epidermal growth factor receptors in lung cancer.

摘要: The initiation of epidermal growth factor receptor (EGFR) kinase activity proceeds via an asymmetric dimerization mechanism in which a “donor” tyrosine domain (TKD) contacts “acceptor” TKD, leading to its activation. In the context ligand-induced dimer, identical wild-type EGFR TKDs are thought assume donor or acceptor roles random manner. Here, we present biochemical reconstitution data demonstrating that activated mutants found lung cancer preferentially role when coexpressed with WT EGFR. Mutated EGFRs show enhanced association EGFR, hyperphosphorylation counterpart. also hyperphosphorylate related erythroblastic leukemia viral oncogene (ErbB) family member, ErbB-2, similar This directional “superacceptor activity” is particularly pronounced drug-resistant L834R/T766M mutant. A 4-A crystal structure this mutant active conformation reveals dimer interface essentially same as Asymmetric formation induces allosteric conformational change subunit. Thus, superacceptor likely arises simply from lower energetic cost associated compared WT, rather than any structural alteration impairs Collectively, these findings define previously unrecognized mode mutant-specific intermolecular regulation for ErbB receptors, knowledge could potentially be exploited therapeutic benefit.